1. Field of the invention
This invention is directed to 2H-pyrido3',2':5,6!thiopyrano4,3,2-cd!indazoles, 2H-pyrido4',3':5,6!thiopyrano4,3,2-cd!indazoles, 2H-pyrido3',4':5,6!thiopyrano4,3,2-cd!indazoles and 2H-pyrido2',3':5,6!thiopyrano4,3,2-cd!indazoles substituted in the positions 2 and 5.
These compounds have been shown to have antitumor activity.
2. Background
Certain 1,4-bis(aminoalkyl)amino!anthracene-9,10-diones have been reported which show antitumor activity in clinical trials. Of particular interest has been ametantrone, 1,4-bis(2-(2-hydroxyethylamino)ethyl)amino!anthracene-9,10-dione and mitoxantrone, 5,8-dihydroxy-1,4-bis(2-(2-hydroxyethylamino)ethyl)amino!anthracene-9,10- dioneZee-Cheng et al., J Med. Chem., 21, 291-4 (1978); Cheng et al., "Progress in Medicinal Chemistry", Ellis, G. P. and West, G. B., eds.; Elsevier: Amsterdam, 1983, vol. 20, pp. 83 and references cited therein!. Mitoxantrone is a broad spectrum oncolytic agent, whose activity is similar to that of the anthracycline antibiotic doxorubicin. Clinical trials have demonstrated that mitoxantrone has particularly promising activity in the treatment of advanced breast cancer, acute leukemia and lymphoma Legha, Drugs of Today, 20, 629 (1984)!. Although animal studies have demonstrated a diminished cardiotoxicity in comparison to doxorubicin, some clinical cardiotoxicity has been observed also with mitoxantrone, mostly in patients previously treated with doxorubicin R. Stuart Harris et al., Lancet, 219, (1984) and references cited therein!.
Ametantrone has been reported to be, in animals, about 10-fold less potent and cardiotoxic than mitoxantrone. Because a delayed toxicity is observed only with mitoxantrone after administration of the two drugs by the i.p. route to non-tumor bearing rats at equieffective antitumor dosages, it is suggested that the presence of the 5,8-dihydroxy substitution in mitoxantrone might be implicated in the delayed deaths Corbett et al., Cancer Chemother. Pharmacol., 6, 161 (1981)!.
In addition, both mitoxantrone and ametantrone have a remarkable myelodepressive toxicity and both compounds show cross-resistance to cell histotypes developing resistance against doxorubicin mediated by overexpression of glycoprotein P. Such a resistance, which is named multidrug resistance (MDR), involves a number of antitumor antibiotics, among which amsacrine and podophyllotoxinic In addition, both mitoxantrone and ametantrone have a remarkable myelodepressive toxicity and both derivatives, and it is one of the main reasons for therapeutic failures in the treatment of solid tumors with said antibiotics.
In an attempt to overcome the above mentioned drawbacks some chromophore modified anthracenediones have been prepared. For example, E. P. Patent Application 103.381 discloses 2-aminoalkyl-5-aminoalkylamino substituted anthra1,9-cd!pyrazol6(2H)-ones (anthrapyrazoles) which are claimed to have antitumor activity. The antitumor activity of said compounds in a number of preclinical models has been reported by H. D. Hollis Showalter et al. J. Med. Chem., 30, 121-131 (1987)!. However anthrapyrazoles are not devoid of toxic side effects, with severe leukopenia (W.H.O. grade 3 and 4) and neutropenia (W.H.O. grade 4) being dose limiting in phase I and phase II clinical trials with the anthrapyrazole CI-941 I. E. Smith et al., J. Clin. Oncol., 9, 2141-2147 (1991)!. Moreover a marked nephrotoxicity is associated with CI-941 treatment in the rat D. Campling and M. E. C. Robbins, Nephrotoxicity, Peter H. Dekker Bach editor, pp. 345-352 (1991), New York; see Chemical Abstract 116: 294n (1992)! and these authors suggest that renal injury may be a clinical problem with anthrapyrazole therapy. In addition recent reports Drugs of the Future, 17, 725 (1992); Judson, I. R. et al., Proc. Amer. Assoc. Cancer Res., 32, abstr. 1059 (1991)! indicate that the anthrapyrazole CI-941 induces irreversible cardiotoxicity in humans, although no symptoms of cardiac failure or acute cardiac events have been reported.
Furthermore, WO94/06795 (31.03.94) describes aza-anthrapyrazole derivatives which are endowed with antitumor activity.
In the attempt to reduce the radical formation "in vivo" by eliminating the "quinonoid" structure, benzothiopyranoindazoles have been prepared H. D. Hollis Showalter et al., J. Med. Chem., 31, 1527-1539 (1988)!. In these compounds a carbonyl group at C-6 position has been replaced by a sulphur atom. A compound of this series, CI-958, has been chosen for development toward clinical trials.
However, the search for newer active analogues is still highly desirable. We have now discovered that the introduction of one nitrogen atom in the positions 7, 8, 9 or 10 of the above mentioned benzothiopyranoindazoles provides 2H-pyrido3',2':5,6!thiopyrano4,3,2-cd!indazoles, 2H-pyrido4',3':5,6!thiopyrano4,3,2-cd!indazoles, 2H-pyrido3',4':5,6!thiopyrano4,3,2-cd!indazoles and 2H-pyrido2',3':5,6!thiopyrano4,3,2-cd!indazoles substituted in the positions 2 and 5, which have showed a marked antitumor activity.